Method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and chlorinated derivatives thereof

ABSTRACT

2-Aminothiophenol is reacted with methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate, and the intermediate methyl (2S,3S)-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionate is cyclized in the presence of methanesulfonic acid, in the same vessel and without isolating said intermediate product, using e.g. chlorobenzene as a solvent.

.Iadd.

This application is a continuation-in-part of application Ser. No.07/408,042, filed Sep. 14, 1989, now U.S. Pat. No. 5,013,835. .Iaddend.

The subject of the present invention is a method for preparing(+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl-2,3-dihydro-5H-1,5-benzothiazepine-4-one,bearing optionally a chlorine atom on the aromatic ring.

These optically pure compounds are synthetic intermediates of compoundswith therapeutic activities, such as(+)-(2S,3S)-3-acetyloxy-5-(2-dimethylaminoethyl)-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-oneand its chlorinated derivatives.

The reaction scheme is shown on the following page. In the formulae, Xdenotes hydrogen or chlorine.

The first step comprises reacting a 2-aminothiophenol derivative ofgeneral formula II with methyl (-).(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate of formula III. A methyl(2S,3S)-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionatederivative of general formula IV is obtained via opening the epoxidering.

The second step comprises the cyclization of this compound in thepresence of an acid.

The reaction principles of each of the two steps are well known.

They are found, for example, in Chem. Pharm. Bull., 18, 2028-2037(1970), where the ester of formula III is used in racemic form. Thefirst step necessitates several hours of heating to 150°-160° C., andafter separation and purification of the ester of formula IV, the secondstep is performed by hydrolyzing this ester and cyclizing the acidobtained in the presence of sulfuric or acetic acid, in refluxingxylene.

U.S. Pat. No. 4,416,819 describes the first step, where the (racemic)ester of formula III reacts with the aminothiophenol (II) in tolueneafter six hours of heating at reflux.

Japanese Patent Application 145160/1986, which describes the synthesisof the optically pure ester of formula III, likewise. ##STR1## describesthe reaction of the latter with aminothiophenol of formula II, undertoluene reflux for 10 hours.

Finally, European Patent Application 0154838 describes among others amethod that combines the two steps. The reactions are performed withoutsolvent, requiring 16 hours of heating to 160° C., and furnishing amixture of optical isomers of the final compound and is intermediate.

Thus it is clear that none of the known methods are suitable foreconomic industrial manufacture of the compounds of formula I, forvarious reasons: poor yields, elevated temperatures, the need to purifythe intermediate and/or final compounds, and long reaction times.

The present invention therefore proposes a method that overcomes thedisadvantages of the known art, and affords the following advantages:

the two reaction steps can be performed in the one and same reactor, sothat emptying and cleaning it between the two steps, or using a secondreactor, is unnecessary (for reasons of convenience, the two steps canbe performed in separate reactors, but anyway it is not necessary toisolate the intermediate ester);

the total yield is high compared with the yields of the known methods;

energy consumption is reduced, in particular during the first step;

the reaction times are short; and

the final compound is pure.

The operating conditions of the method according to the invention, whichmake it possible to attain all the advantages listed above, aredescribed below.

The starting ester of formula III is used in optically pure form. It isdescribed in Japanese Patent Applications 145159/1986, 145160/1986 and145174/1986.

The possibility of carrying out the two steps of the reaction in thesame vessel, without evacuation or intermediate transfer to anothervessel, is due to the selection of a unique solvent which is highlysuitable for each of the steps.

Specific solvents for each of the two steps are naturally already known(dichloroethane, toluene, xylene, etc.), but they are different for eachstep and so do not permit the entire method to take place within thesame reactor. The solvents to be used according to the invention arechlorinated organic solvents having a boiling point of more than 70° C.Examples of suitable solvents are 1,2,3-trichloropropane,dichlorobenzenes and, preferably, chlorobenzene.

These solvents are not only--and unexpectedly--highly favorable to agood overall yield, but further/more they are so efficient that thefirst step necessitates heating only for startup, because the exothermicnature of the reaction is sufficient for it to be maintained withoutadding external energy. This particular feature was entirelyunforeseeable, because it had never been found with other solvents.

Additionally, the use of these solvents promotes the threoerythroselectivity of the first step. With other solvents, it is in fact foundthat an unfavorable mixture of diastereoisomers of formula IV isobtained.

Another particular feature of the invention is due to the catalyst usedin the second step. While it is known that cyclization takes placebetter in an acid medium (sulfuric or acetic), the catalyst to be usedaccording to the invention is selected from methanesulfonic acid,phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid,perchloric acid, paratoluenesulfonic acid. The preferred catalyst ismethanesulfonic acid.

These acids, which make it possible to obtain an excellent yield of thecyclized compound (I), are simple to add to the reaction medium as soonas the first step is completed.

The following examples provide a detailed illustration of the methodaccording to the invention.

EXAMPLE 1

In an enameled, 25-liter reactor purged with nitrogen, are introduced 3kg of methyl(-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate and 10 lof chlorobenzene, and the mixture is heated to 100° C. Heating isstopped, and a solution of 1900 g of 2-aminothiophenol in 1.51 ofchlorobenzene is introduced in the space of 30 minutes, so as not toallow the temperature to exceed 120° C., and 3.5 l of chlorobenzene isalso added to rinse the inlet funnel and the tubing.

The temperature is kept at approximately 115° C. for a further 30minutes, and then 37.5 ml of methanesulfonic acid is added, and themixture is heated at reflux for 8 hours, with elimination of a mixtureof methanol and chlorobenzene by distillation, in order not to allow thetemperature to drop below 132° C. (the boiling point of chlorobenzene).

The heating is stopped; the mixture is allowed to return to 20° C.; itis chilled to 5° C. for one hour; and the crystals formed are filtered,rinsed with chlorobenzene, and are dried in a vacuum at 100° C.

A yield of 3463 g of pure(+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-oneis obtained. Melting point: 200.3°-201.8° C. [α]_(D) ²⁰ =+114° (c=0.1;DMF).

EXAMPLE 2

In a 1 liter flask under an argon atmosphere are introduced 50 g ofmethyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate and 350 ml ofdichlorobenzene (a commercial mixture of o-, m- and p-isomers) and themixture is heated at 115° C. Then, in the space of 30 minutes, so as notto allow the temperature to exceed 120° C., 31.8 g of 2-aminothiophenolare introduced.

The temperature is kept at 120° C. for a further 30 minutes, and then0.62 ml of methanesulfonic acid is added, and the mixture is heated at150° C. for 3 hours (the reaction is completed after 2 hours).

The mixture is allowed to cool; it is chilled to 5° C. for one hour; andthe crystals are filtered and washed with dichlorobenzene and dried invacuo. 49.5 g of pure(+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-oneare obtained. Melting point: 203°-204° C.

EXAMPLE 3

18.8 g of 2-aminothiophenol are added dropwise to a solution of 30 g ofmethyl(-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate in 200 ml of1,2,3-trichloropropane at 110°-115° C. After 30 minutes 0.35 g ofmethanesulfonic acid is added, and the mixture is heated at 145°-150° C.for 6 hours. The mixture is allowed to cool, then chilled and filtered;the crystals are washed with 1,2,3-trichloropropane, and dried in vacuoat 50° C.

33.8 g of pure(+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-oneare obtained. Melting point: 202.8°-204.1° C.

EXAMPLE 4

In the same way as in Example 1, the reaction between2-amino-5-chlorothiophenol and methyl(-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate affords(+)-(2S,3S)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one.Melting point: 237°-241° C. [α]_(D) ²⁰ =+91.9° (c=0.1; DMF).

We claim:
 1. A method for preparing a compound of the general formula(I) ##STR2## wherein X is hydrogen or chlorine, said method consistingessentially of: reacting a compound of the general formula (II) ##STR3##with a compound of formula (III) in optically pure levorotatory form##STR4## to obtain an intermediate compound of general formula (IV)##STR5## .[.; and then,.]. ; and then, without isolating saidintermediate,cyclizing the intermediate compound wherein saidcyclization is effected in the presence of acid, and wherein saidreacting and cyclizing steps are performed in the presence of .[.asolvent selected from the group consisting of chlorinated organicsolvents that have boiling points greater than 70°C.]..Iadd.chlorobenzene. .Iaddend.
 2. The method of claim 1, wherein Xis hydrogen. .[.3. The method of claim 1, wherein the solvent ischlorobenzene..]. .[.4. The method of claim 1, wherein the solvent is adichlorobenzene..]. .[.5. The method of claim 1, wherein the solvent is1,2,3-trichloropropane..].
 6. The method of claim 1, wherein said acidis methane-sulfonic acid.